Abstract Nearly 90% of patients who suffer an out-of-hospital cardiac arrest (CA) die. This leading cause of unexpected and sudden death in the US results in an enormous emotional, psychological and financial burden to hundreds of thousands of families and communities across America annually. Relative to the many potentially lethal disease states such as cancer, stroke, sepsis, and trauma, CA survival rates have barely improved since 1960 when manual standard (S) was first described. Over the past 25 years, the applicants have discovered and developed new approaches, techniques and devices to increase cerebral and coronary blood flow and improve neurologically-sound survival after CA. With prior NIH SBIR support they developed the impedance threshold device (ITD), performed animal and clinical trials, and ultimately obtained FDA approval for manual active compression decompression (ACD) plus ITD, the first device ever approved by the FDA to increase the likelihood of survival after CA. Despite this progress, further innovation is needed to substantively improve successful outcomes for more Americans. This application is focused on a new discovery that elevation of the head and thorax during ACD + ITD CPR results in a striking decrease in intracranial pressures and an increase in cerebral and coronary perfusion pressures. These findings, due to the effects of gravity when the head and heart are elevated, have the potential to significantly further enhance cerebral and coronary blood flow and improve overall survivability. The proposed research in an animal model of cardiac arrest is focused on demonstrating proof-of-concept that a new head up CPR device, when used in combination with ACD + ITD CPR, is able to significantly improve blood flow to the heart and brain safely and effectively increase 48-hour survival in an animal model of prolonged CA. We further propose to assess the ergonomics and human factors associated with a light-weight human prototypic head up CPR device in manikins and human cadavers with help of professional firefighters. This novel and approach could increase neurologically-favorable survival rates for >10,000 more Americans annually due to greater blood flow and lower intracranial pressure afforded by gravity-enhanced head up CPR.